Development of reverse phase protein microarrays for clinical applications and patient-tailored therapy

While genomics provide important information about the somatic genetic changes, and RNA transcript profiling can reveal important expression changes that correlate with outcome and response to therapy, it is the proteins that do the work in the cell. At a functional level, derangements within the proteome, driven by post-translational and epigenetic modifications, such as phosphorylation, is the cause of a vast majority of human diseases. Cancer, for instance, is a manifestation of deranged cellular protein molecular networks and cell signaling pathways that are based on genetic changes at the DNA level. Importantly, the protein pathways contain the drug targets in signaling networks that govern overall cellular survival, proliferation, invasion and cell death. Consequently, the promise of proteomics resides in the ability to extend analysis beyond correlation to causality. A critical gap in the information knowledge base of molecular profiling is an understanding of the ongoing activity of protein signaling in human tissue: what is activated and “in use” within the human body at any given point in time. To address this gap, we have invented a new technology, called reverse phase protein microarrays, that can generate a functional read-out of cell signaling networks or pathways for an individual patient obtained directly from a biopsy specimen. This “wiring diagram” can serve as the basis for both, selection of a therapy and patient stratification.

Senataxin plays an essential role with DNA damage response proteins in meiotic recombination and gene silencing

Senataxin, mutated in the human genetic disorder ataxia with oculomotor apraxia type 2 (AOA2), plays an important role in maintaining genome integrity by coordination of transcription, DNA replication, and the DNA damage response. We demonstrate that senataxin is essential for spermatogenesis and that it functions at two stages in meiosis during crossing-over in homologous recombination and in meiotic sex chromosome inactivation (MSCI). Disruption of the Setx gene caused persistence of DNA double-strand breaks, a defect in disassembly of Rad51 filaments, accumulation of DNA:RNA hybrids (R-loops), and ultimately a failure of crossing-over. Senataxin localised to the XY body in a Brca1-dependent manner, and in its absence there was incomplete localisation of DNA damage response proteins to the XY chromosomes and ATR was retained on the axial elements of these chromosomes, failing to diffuse out into chromatin. Furthermore persistence of RNA polymerase II activity, altered ubH2A distribution, and abnormal XY-linked gene expression in Setx⁻/⁻ revealed an essential role for senataxin in MSCI. These data support key roles for senataxin in coordinating meiotic crossing-over with transcription and in gene silencing to protect the integrity of the genome.

Functional role for senataxin, defective in ataxia oculomotor apraxia type 2, in transcriptional regulation

Ataxia oculomotor apraxia type 2 (AOA2) is an autosomal recessive neurodegenerative disorder characterized by cerebellar ataxia and oculomotor apraxia. The gene mutated in AOA2, SETX, encodes senataxin, a putative DNA/RNA helicase which shares high homology to the yeast Sen1p protein and has been shown to play a role in the response to oxidative stress. To investigate further the function of senataxin, we identified novel senataxin-interacting proteins, the majority of which are involved in transcription and RNA processing, including RNA polymerase II. Binding of RNA polymerase II to candidate genes was significantly reduced in senataxin deficient cells and this was accompanied by decreased transcription of these genes, suggesting a role for senataxin in the regulation/modulation of transcription. RNA polymerase II-dependent transcription termination was defective in cells depleted of senataxin in keeping with the observed interaction of senataxin with poly(A) binding proteins 1 and 2. Splicing efficiency of specific mRNAs and alternate splice-site selection of both endogenous genes and artificial minigenes were altered in senataxin depleted cells. These data suggest that senataxin, similar to its yeast homolog Sen1p, plays a role in coordinating transcriptional events, in addition to its role in DNA repair.

Follicular variant of papillary thyroid carcinoma : a diagnostic challenge for clinicians and pathologists

The follicular variant of papillary thyroid carcinoma (FVPTC) presents a type of papillary thyroid cancer that has created continuous diagnosis and treatment controversies among clinicians and pathologists. In this review, we describe the nomenclature, the clinical features, diagnostic problems and the molecular biology of FVPTC. It is important for clinicians to understand this entity as the diagnosis and management of this group of patient may be different from other patients with conventional PTC. The literature suggests that FVPTC behaves in a way similar, clinically, to conventional papillary thyroid carcinoma. However, there are some genotypic differences which may characterise this neoplasm. These parameters may account for the phenotypic variation described by some scientists in this type of cancer. Further understanding can only be achieved by defining strict pathological criteria, in-depth study of the molecular biology and long term follow-up of the optional patients with FVPTC.

Withholding and withdrawing life-sustaining medical treatment

• At common law, a competent adult can refuse life-sustaining medical treatment, either contemporaneously or through an advance directive which will operate at a later time when the adult’s capacity is lost. • Legislation in most Australian jurisdictions also provides for a competent adult to complete an advance directive that refuses life-sustaining medical treatment. • At common law, a court exercising its parens patriae jurisdiction can consent to, or authorise, the withdrawal or withholding of life-sustaining medical treatment from an adult or child who lacks capacity if that is in the best interests of the person. A court may also declare that the withholding or withdrawal of treatment is lawful. • Guardianship legislation in all jurisdictions allows a substitute decision-maker, in an appropriate case, to refuse life-sustaining medical treatment for an adult who lacks capacity. • In terms of children, a parent may refuse life-sustaining medical treatment for his or her child if it is in the child’s best interests. • While a refusal of life-sustaining medical treatment by a competent child may be valid, this decision can be overturned by a court. • At common law and generally under guardianship statutes, demand for futile treatment need not be complied with by doctors.

A digital watermarking framework with application to medical image security

Dealing with digital medical images is raising many new security problems with legal and ethical complexities for local archiving and distant medical services. These include image retention and fraud, distrust and invasion of privacy. This project was a significant step forward in developing a complete framework for systematically designing, analyzing, and applying digital watermarking, with a particular focus on medical image security. A formal generic watermarking model, three new attack models, and an efficient watermarking technique for medical images were developed. These outcomes contribute to standardizing future research in formal modeling and complete security and computational analysis of watermarking schemes.

Beyond Wearables : Experiences and Trends in Design of Portable Medical Devices

The use of Portable Medical Devices (PMDs) has become increasingly widespread over the last few years. A combination of factors; including advances in technology, the pressure to reduce public health costs and the desire to make health solutions accessible to a wider patient base are contributing to the growth in the PMD market. Design has a clear role to play in the current and future context of the PMD landscape. In this paper, we identify emerging trends in the design of PMDs; including changes in the form, purpose and mode of use, and explore how these trends are likely to fundamentally impact the nature of healthcare and the patient experience from an experience design perspective. We conclude by identifying a research opportunity for design within the healthcare and PMD context.

No genetic bottleneck in Plasmodium falciparum wild-type Pfcrt alleles reemerging in Hainan Island, China, following high-level chloroquine resistance

Chloroquine-resistant Plasmodium falciparum was highly prevalent in Hainan, China, in the 1970s. Twenty-five years after cessation of chloroquine therapy, the prevalence of P. falciparum wild-type Pfcrt alleles has risen to 36% (95% confidence interval, 22.1 to 52.4%). The diverse origins of wild-type alleles indicate that there was no genetic bottleneck caused by high chloroquine resistance.

Speckle-type POZ protein mutations interrupt tumor suppressor function of speckle-type POZ protein in prostate cancer by affecting androgen receptor degradation

Large scale exome sequencing studies have revealed regions of the genome, which contribute to the castrate resistant prostate cancer (CRPC) phenotype. [1],[2],[3] Such studies have identified mutations in genes, which may have diagnostic/prognostic potential, or which may be targeted therapeutically. Two of these genes include the androgen receptor (AR) and speckle-type POZ protein (SPOP) genes. However, the findings from these exome sequencing studies can only be translated therapeutically once the functional consequences of these mutations have been determined. Here, we highlight the recent study by An et al. [4] which investigated the functional effects of mutations in the SPOP gene that were identified in the aforementioned exome sequencing studies, particularly in the context of SPOP-mediated degradation of the AR.

Female genital cutting : An overview of Australian legal principles, ethical controversies, and medical, legal and social challenges

Female genital cutting (also often called female genital mutilation, or female circumcision) is a cultural practice that originated thousands of years ago. Female genital cutting has various forms, some of which are more invasive than others, but all of which produce health, legal and social consequences for those involved. Due to patterns of immigration in Australia, especially since the 1990s, there are women in Australia who have experienced female genital cutting. There may be some families, or some parents, who still hold a cultural commitment to female genital cutting. As a result, female genital cutting presents complex legal, ethical, medical and social challenges in contemporary Australian society. Medical practitioners and other health and welfare workers may encounter women who have experienced genital cutting and who require treatment for its sequelae. Currently, legislative frameworks for female genital cutting vary across states and territories, including the penalties for conducting it, and for removing a child for the purpose of conducting it outside Australia. This presentation provides an overview of the history, nature and consequences of the various forms of female genital cutting, and of the major Australian legal principles, ethical controversies, and medical, legal and social challenges in this field.

Doctors' knowledge of the law on withholding and withdrawing life-sustaining medical treatment

Objectives To examine the level of knowledge of doctors about the law on withholding and withdrawing life-sustaining treatment from adults who lack decision-making capacity, and factors associated with a higher level of knowledge. Design, setting and participants Postal survey of all specialists in emergency medicine, geriatric medicine, intensive care, medical oncology, palliative medicine, renal medicine and respiratory medicine on the AMPCo Direct database in New South Wales, Victoria and Queensland. Survey initially posted to participants on 18 July 2012 and closed on 31 January 2013. Main outcome measures Medical specialists’ levels of knowledge about the law, based on their responses to two survey questions. Results Overall response rate was 32%. For the seven statements contained in the two questions about the law, the mean knowledge score was 3.26 out of 7. State and specialty were the strongest predictors of legal knowledge. Conclusions Among doctors who practise in the end-of-life field, there are some significant knowledge gaps about the law on withholding and withdrawing life-sustaining treatment from adults who lack decision-making capacity. Significant consequences for both patients and doctors can flow from a failure to comply with the law. Steps should be taken to improve doctors’ legal knowledge in this area and to harmonise the law across Australia.

The development and evaluation of a medical imaging training immersive environment

Introduction A novel realistic 3D virtual reality (VR) application has been developed to allow medical imaging students at Queensland University of Technology to practice radiographic techniques independently outside the usual radiography laboratory. Methods A flexible agile development methodology was used to create the software rapidly and effectively. A 3D gaming environment and realistic models were used to engender presence in the software while tutor-determined gold standards enabled students to compare their performance and learn in a problem-based learning pedagogy. Results Students reported high levels of satisfaction and perceived value and the software enabled up to 40 concurrent users to prepare for clinical practice. Student feedback also indicated that they found 3D to be of limited value in the desktop version compared to the usual 2D approach. A randomised comparison between groups receiving software-based and traditional practice measured performance in a formative role play with real equipment. The results of this work indicated superior performance with the equipment for the VR trained students (P = 0.0366) and confirmed the value of VR for enhancing 3D equipment-based problem-solving skills. Conclusions Students practising projection techniques virtually performed better at role play assessments than students practising in a traditional radiography laboratory only. The application particularly helped with 3D equipment configuration, suggesting that teaching 3D problem solving is an ideal use of such medical equipment simulators. Ongoing development work aims to establish the role of VR software in preparing students for clinical practice with a range of medical imaging equipment.

Psychological health of medical and dental students in Saudi Arabia : a longitudinal study

Introduction: Many studies have indicated the poor psychological health of medical and dental students. However, few studies have assessed the longitudinal trajectory of that psychological health at different times in an academic year. Aim: To evaluate the positive and negative aspects of psychological health among preclinical medical and dental students in Saudi Arabia prospectively. Methods: A total of 317 preclinical medical and dental students were recruited for a longitudinal study design from second and third-year students at Umm Al-Qura University in the 2012-2013 academic year. The students were assessed at the middle of the first term and followed up after 3-monthes at the beginning of the second term. Questionnaires included assessment of depression, anxiety, stress, self-efficacy, and satisfaction with life. Results: Depression, anxiety, stress, and satisfaction with life were improved significantly at the beginning of the second term, whereas self-efficacy did not change significantly. The medical, female, and third-year student subgroups had the most significant changes. Depression and stress were significantly changed at the beginning of the second term in most demographic subgroups. Conclusion: Preclinical medical and dental students have different psychological health levels at different times of the same academic year. It is recommended to consider time of data collection when analyzing the results of such studies.

Social support, self-efficacy, trauma and well-being in emergency medical dispatchers

Emergency Medical Dispatchers (EMDs) respond to crisis calls for ambulance; they dispatch paramedics and provide emotional and medical assistance to callers. Despite the stressful nature and exposure to potentially traumatising events in this role, there has been no published research specifically investigating well-being or posttraumatic growth among EMDs. Extrapolating from research conducted among other emergency services workers (e. g., paramedics, police), literature attests to the importance of self efficacy and social support in promoting mental health in emergency service workers. Therefore, this study assessed the impact of self efficacy, and giving and receiving social support on psychological well-being, posttraumatic growth (PTG), and symptoms of posttraumatic stress disorder (PTSD). Sixty EMDs (50% response rate) completed an online questionnaire. Three hierarchical multiple regression analyses were conducted to ascertain predictors of well-being, PTG and PTSD. Receiving social support emerged as a significant positive predictor of well-being and PTG, and a significant negative predictor of PTSD. Self efficacy was found to significantly and positively predict well-being, and shift-work was found to significantly and negatively predict PTSD. These results highlight that self efficacy and receiving social support are likely to be important for enhancing well-being within this population, and that receiving social support is also likely to facilitate positive post-trauma responses. Such findings have implications for the way emergency service personnel are educated with reference to aspects of mental health and how best to support personnel in order to achieve optimal mental health outcomes for all.